Prostate cancer is the most common form of cancer among males. Overwhelming clinical evidence shows that human prostate cancer has the propensity to metastasize to bone, and the disease appears to progress inevitably from androgen dependent to androgen refractory status, leading to increased patient mortality. This prevalent disease is currently the second leading cause of cancer death among men in the U.S.
In spite of considerable research into therapies for the disease, prostate cancer remains difficult to treat. Commonly, treatment is based on surgery and/or radiation therapy, but these methods are ineffective in a significant percentage of cases. Two previously identified prostate specific proteins—prostate specific antigen (PSA) and prostatic acid phosphatase (PAP)—have limited therapeutic and diagnostic potential. For example, serum PSA concentrations do not always correlate well with the presence of prostate cancer, being positive in a percentage of non-prostate cancer cases, and serum PSA concentrations do not correlate with cancer severity.
Current clinical practice includes routine prostate cancer screening in men over the age of forty for prostate cancer. This screening involves looking for the protein prostate specific antigen (PSA) in the blood. This test does not always identify patients with prostate cancer and can't identify aggressive prostate cancer. Patients exhibit extreme variation in the progression of their prostate cancer. In some the cancer remains confined to the prostate and causes no harm to the patient. In others, the cancer spreads quickly throughout the body, especially to the bones. There are no accurate methods to determine the aggressiveness of prostate cancer. Therefore, the physician treating this disease does not have reliable ways to determine whether the prostate cancer will spread. The current treatments for prostate cancer often have significant negative effects on patient quality of life. This situation makes it difficult for the physician to make proper treatment decisions.
Using the technique of differential display polymerase chain reaction, it was found that the cytokine, macrophage migration inhibitory factor (MIF), is one gene whose expression is altered in metastatic prostate cancer when compared to normal tissue (Meyer-Siegler et al. (1996), Urology 48: 448-452).
MIF was first described thirty years ago and was designated as a cytokine, a chemical mediator, which regulates cell growth by inducing the expression of specific target genes. The initial described function of MIF was as a regulator of inflammation and immunity. It is expressed in the brain, and eye lens, is a delayed early response gene in fibroblasts, and it has been reported that this protein can be found in prostate tissues. MIF has been shown to be a pituitary, as well as macrophage cytokine and a critical mediator of septic shock. Recent studies also suggest that MIF may have an autocrine function for embryo development and is produced by the Leydig cells of the testes. Thus, it appears that this cytokine may play a fundamental role in cell growth regulation and possibly development.
U.S. Pat. No. 6,043,044 discloses the use of prostate tissue extracts as a patient sample to determine the amount of MIF. Immuno- and RNA blot analysis performed using homogenized tissue that contains variable proportions of epithelial and stromal cells still determined significant differences in the levels of MIF protein produced by metastatic tissue (490.3+/−71.3 ng/mg total protein). In practice this test was unreliable and difficult to perform because of contamination with surrounding connective and stromal tissue. It does not have utility in patient diagnosis or prognosis. Further, the patent does not mention or correlate serum MIF levels with prostate cancer.
There are currently very few genetic methods available for the diagnosis and prevention of prostate cancer. Thus, the identification of genetic polymorphisms controlling MIF expression, that are responsible for predisposition of prostate cancer would provide for a better understanding of the mechanisms of cancer causation (including ethnic and individual susceptibility), and ultimately lead to ways of prostate cancer prevention. The present invention addresses these disadvantages present in the prior art and provides an improved assay with commercial application that is less invasive than that of the prior art.